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lecture14 - Multiscale model of the lac operon Villa et...

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Multiscale model of the lac operon. Villa et al. (2005) Structural dynamics of the lac repressor-DNA complex revealed by a multiscale simulation. PNAS 102: 6783-6788. Background: The lac operon is a cluster of genes in the E. coli genome that encode proteins involved in lactose metabolism. The lac repressor (LacI) is a DNA-binding protein that inhibits the expression of the operon in the absence of lactose. This study used a combined atom-filament model of a LacI-DNA complex to investigate the structural dynamics of the repressor. Jay Taylor (ASU) APM 530 - Lecture 14 Fall 2010 1 / 24
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Multiscale model of the lac operon. The lac operon contains three protein-coding genes: lacZ encodes β -galactosidase , which cleaves lactose into galactose and glucose; lacY encodes a lactose permease , which pumps lactose into the cell; lacA encodes a thiogalactoside transacetylase . Jay Taylor (ASU) APM 530 - Lecture 14 Fall 2010 2 / 24
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Multiscale model of the lac operon. The lac genes are co-regulated. The three lac genes share a common promoter and are transcribed as a single polycistronic mRNA. The lac operon is transcribed at very low levels whenever lactose is absent. (This is thought to prevent the wasteful production of enzymes that aren’t needed.) The operon is also transcribed at low levels when glucose is present, even if lactose is also present. (Glucose may be a preferred source of energy.) The lac operon is transcribed at high levels if lactose is present and glucose is absent. Jay Taylor (ASU) APM 530 - Lecture 14 Fall 2010 3 / 24
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Multiscale model of the lac operon. LacI inhibits transcription when lactose is absent. In the absence of lactose, LacI binds to two operator sequences that flank the promoter. This interferes with binding of RNA polymerase to the lac promoter and blocks most transcription of the operon. Figure from Wilson et al. (2007) Cell. Mol. Life Sci. 64: 3-16. Jay Taylor (ASU) APM 530 - Lecture 14 Fall 2010 4 / 24
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Multiscale model of the lac operon. The operon is weakly transcribed when glucose is present. Allolactose is a product of lactose metabolism, which occurs at low levels even when the repressor is bound to the operator. Binding of allolactose to LacI lowers its a nity for the operator. However, dissociation of LacI from the operator only results in a small increase in lac transcription if glucose is present in the cell. Jay Taylor (ASU) APM 530 - Lecture 14 Fall 2010 5 / 24
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Multiscale model of the lac operon. The operon is strongly expressed if lactose is present and glucose is absent. Absence of glucose within the cell leads to an increase in cyclic AMP levels.
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